title: Inhalable metal-rich air particles and histone H3K4 dimethylation and H3K9 acetylation in a cross-sectional study of steel workers.
abstract: BACKGROUND
  Epidemiology investigations have linked exposure to ambient and occupational air particulate matter (PM) with increased risk of lung cancer. PM contains carcinogenic and toxic metals, including arsenic and nickel, which have been shown in in vitro studies to induce histone modifications that activate gene expression by inducing open-chromatin states. Whether inhalation of metal components of PM induces histone modifications in human subjects is undetermined.
  
  
  OBJECTIVE
  We investigated whether the metal components of PM determined activating histone modifications in 63 steel workers with well-characterized exposure to metal-rich PM.
  
  
  METHODS
  We determined histone 3 lysine 4 dimethylation (H3K4me2) and histone 3 lysine 9 acetylation (H3K9ac) on histones from blood leukocytes. Exposure to inhalable metal components (aluminum, manganese, nickel, zinc, arsenic, lead, iron) and to total PM was estimated for each study subject.
  
  
  RESULTS
  Both H3K4me2 and H3K9ac increased in association with years of employment in the plant (p-trend = 0.04 and 0.006, respectively). H3K4me2 increased in association with air levels of nickel [β = 0.16; 95% confidence interval (CI), 0.03-0.3], arsenic (β = 0.16; 95% CI, 0.02-0.3), and iron (β = 0.14; 95% CI, 0.01-0.26). H3K9ac showed nonsignificant positive associations with air levels of nickel (β = 0.24; 95% CI, -0.02 to 0.51), arsenic (β = 0.21; 95% CI, -0.06 to 0.48), and iron (β = 0.22; 95% CI, -0.03 to 0.47). Cumulative exposures to nickel and arsenic, defined as the product of years of employment by metal air levels, were positively correlated with both H3K4me2 (nickel: β = 0.16; 95% CI, 0.01-0.3; arsenic: β = 0.16; 95% CI, 0.03-0.29) and H3K9ac (nickel: β = 0.27; 95% CI, 0.01-0.54; arsenic: β = 0.28; 95% CI, 0.04-0.51).
  
  
  CONCLUSIONS
  Our results indicate histone modifications as a novel epigenetic mechanism induced in human subjects by long-term exposure to inhalable nickel and arsenic.
authors.affiliation: Department of Environmental and Occupational Health, Università di Milano and Istituto Di Ricovero e Cura a Carattere Scientifico, and Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cantone
authors.forename: Francesco
authors.initials: F
authors.lastname: Nordio
authors.forename: Lifang
authors.initials: L
authors.lastname: Hou
authors.forename: Pietro
authors.initials: P
authors.lastname: Apostoli
authors.forename: Matteo
authors.initials: M
authors.lastname: Bonzini
authors.forename: Letizia
authors.initials: L
authors.lastname: Tarantini
authors.forename: Laura
authors.initials: L
authors.lastname: Angelici
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
authors.forename: Antonella
authors.initials: A
authors.lastname: Zanobetti
authors.forename: Joel
authors.initials: J
authors.lastname: Schwartz
authors.forename: Pier A
authors.initials: PA
authors.lastname: Bertazzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Baccarelli
mesh_terms: D000107:Acetylation; D000328:Adult; D000393:Air Pollutants / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D044127:Epigenesis, Genetic; D006657:Histones / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007558:Italy; D007962:Leukocytes / Q000737:chemistry; D008297:Male; D008669:Metallurgy; D008670:Metals / Q000032:analysis*; D008745:Methylation; D008875:Middle Aged; D016273:Occupational Exposure; D052638:Particulate Matter / Q000032:analysis*; D011499:Protein Processing, Post-Translational
chemical_list: D000393:Air Pollutants; D006657:Histones; D008670:Metals; D052638:Particulate Matter